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Chapter 2

The role of the sympathoadrenal system in exercise

Exercise calls for an acute increase in oxygen and fuel supply to the contractingmuscle, and these needs are met through the sympathoadrenal (SA) activation ofcardiorespiratory system and through the release and increased utilization of metabolicfuels. Increased metabolism during exercise can deplete fuel resources and exceed thecapacity of homeostatic mechanisms to maintain constancy of interior environment.During the recovery from exercise, the parasympathetic (PS) and enteric divisions of theautonomic nervous system (ANS) coupled with various behavioral responses correctthe deviations in the internal environment and mediate trophic and growth-promotingfunctions.

Endocrine messengers control many of the same functions as does ANS inexercise. Although endocrine and autonomic systems are capable of acting in isolation,a fact that has fostered an artificial notion of their functional separation, in reality theywork in concert and engage in complex reciprocal interactions. The ANS plays a centralrole in coordinating the neural and hormonal responses to exercise and recovery fromexercise. Although the sympathetic (S) activation usually produces "fear, fight, or flightresponse" (Cannon, 1929), that is, a global activation of a large number of functions, itcan also differentially activate only some actions in response to particular stressorssuch as hypoglycemia (Young et al 1984). Autonomic, endocrine and behavioralcompensatory responses cooperate in regulation of the internal environment. Thischapter addresses the functional role of the ANS and its involvement and interactionswith the chemical messengers in exercise.

Autonomic nervous system controls visceral functions necessary for themaintenance of the internal environment. It consists of three divisions: sympathetic(SNS), parasympathetic (PNS), and enteric (ENS). The functions of the three divisionsof the ANS are to increase cardiorespiratory function and metabolism, biosyntheticprocesses, and nutrient digestion and absorbtion, respectively. The S and PS divisionsinclude receptors, sensory nerves and associated ganglia, central nervous centerssubserving integration of autonomic responses, and motor nerves and associatedganglia innervating the smooth muscles and endocrine and exocrine glands (theviscera), although traditionally only the motor component of this complex system hasbeen recognized as ANS and discussed. The viscera are the origin of dual sensoryinput to the central nervous system via S and PS afferent neurons that travel along withefferent fibers in respective autonomic nerves. S receptors sense pain and PS receptorsmonitor chemical, endocrine and mechanical changes in the visceral organs. Thesmooth muscles and endocrine and exocrine glands receive dual motor innervationfrom both S and PS neurons with the exception of sweat glands which receive only Sinnervation.

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Another feature of the ANS is that the autonomic efferent nervesconsist of two nerve cells, a preganglionic and a postganglionic neuron (Figure 16). ThePS preganglionic cells have longer axons than the S pregangionic neurons and synapsewith postgangionic neurons in ganglia that lie close to, or within, the walls of smoothmuscles and glands. The S preganglionic cells are shorter and form synapses in theganglia in paired paravertebral sympathetic trunks adjacent to the spinal cord or inprevertebral ganglia (solar plexus) located at the points where celiac, superior, andinferior mesenteric arteries branch from the aorta.

Figure 16. Composition and neurotransmitters of autonomic motor nerves.

The autonomic efferent nerves consist of a preganglionic and a postganglionic cell.ACH is the neurotransmitter in preganglionic SNS and PNS cells, and it activatesnicotinic receptors (NR) on postganglionic cells. Preganglionic PS cells are longer thanS preganglionic cells because S ganglia are located some distance from target tissuesand PS ganglia are located adjacent or inwalls of target tissues. Postganglionic PScells use ACH as a messenger and it acts muscarinic receptors (MR). Postganglionic Sneurons use NE as neurotransmitter, and adrenal medullary cells (developmentallyderived from S postganglionic cells), a mixture of NE and E. Catecholamines (NE andE) activate adrenergic receptors (AR).

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Both types of preganglionic neurons use ACH as a neurotransmitter and activatenicotinic cholinergic receptors on postganglionic neurons (Figure 16). Thepostganglionic PS neurotransmitter is ACH which activates muscarinic cholinergicreceptors on target cells. The S postganglionic neurons release NE and predominantlyact on alpha adrenergic receptors on target cells. The exception are fibers to the sweatglands which, like the postganglionic PS neurons, release ACH as a neurotransmitter

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and act on muscarinic receptors. The chromaffin cells of the adrenal medulladifferentiate under the influence of cortisol into endocrine cells capable of converting NEinto E (Figure3). In addition to NE, other chemical messengers have been found insympathetic postganglionic neurons. The neuropeptide Y (NPY, Pernow & Lundberg,1988) and the ATP (Burnstock & Kennedy 1986) are colocalized with NE and areimplicated in vasomotor control. The calcitonin gene-related peptide (CGRP) and thevasoactive intestinal polypeptide (VIP) are colocalized with ACH (Landis & Fredieu1986) and participate in sudomotor control.

The sympathetic division of the ANS.

The S afferents transmit pain or nociceptive information from the viscera in Snerves to the higher brain centers where it reaches consciousness (Cervero &Foreman, 1990), and their cell bodies are in segmental dorsal root ganglia (Figure 17).In contrast to PNS, S afferent input contributes only 20% of fibers to the splanchnicnerves, and most of these fibers are unmyelinated. The S sensory fibers project tolaminae I and V in the the spinal gray matter of the thoracic and upper two lumbar spinalsegments. Here they are joined by ten times more numerous sensory fibers fromreceptors in the muscles and the skin. Because of the quantitatively limited afferent Sinput and convergence of visceral and the more numerous somatic afferents, visceralpain is generally referred to skin areas. The heart pain in angina pectoris is felt in thesuperficial areas of arms and upper chest, while the pain in esophagus, gall bladder andduodenum is referred to the overlying superficial areas of the body (Wall & Melzack,1985).

The visceral nociceptive information is transmitted in several centripetalpathways to the higher brain centers (Figure 18) from where the autonomic, emotional,and behavioral responses are organized. The lateral (LSTT) and medial spinothalamictracts (MSTT) carry, respectively, the information about the location of the pain fromneurons in laminae I and V, and about tonic aspects of pain, associated withmotivational and emotional responses, from deeper parts of spinal gray matter to theventroposterolateral and medial thalamus, respectively (Figure 18). The spinoreticulartract to pontine reticular formation, and the spinomesencephalic tract to brachiumconjunctivum (BC) and the periaqueductal gray (PAG) in the pons, that end in thalamusand cortical pain areas, are additional relays for pain . Pain afferents also reach thelateral hypothalamic area (LHA) and brainstem nuclei (nucleus of the tractus solitarius,NTS and parabrachial nucleus (PB), that are involved in the central integration ofautonomic function (Menetrey & Basbaum, 1987).

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Figure 17. Anatomical arrangement of the S nerves

The arrangement of afferent and efferent (right) S nerves form a spinal reflex arc. Thebodies of visceral afferent neurons (left) are located in the dorsal root ganglia, and theircentral dendrites synapse with neurons in laminae I and V of the gray matter in thespinal dorsal horn. Their peripheral dendrite travels through the white ramus (WR) ofthe spinal nerve, the S ganglion, and splanchnic nerve to peripheral pain receptors.PS afferents can make contact with and influence postganglionic S neurons inprevertebral ganglia. S neurons that innervate blood vessels of the skin and muscle(A) terminate in the paravertebral ganglia. Their postganglionic cell leaves the S trunkin gray communicating rami (GR) and reach the skin in segmental somatic nerves.Preganglionic S neurons that innervate the gastrointestinal tract (B) traverse theparavertebral ganglia to form synapses with postganglionic cells in prevertebral gangia.Spinal internuncial neurons connect afferent and preganglionic neurons and are theanatomical basis of the simplest autonomic reflexes.

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Figure 18. Projections of the afferent S fibers

S fibers carry information about visecral pain from laminae I and V of the spinal graymatter to the thalamus (A) in the lateral and medial spinothalamic tracts, to thebrainstem reticular formation (B) in the spinoreticular tract, and to the BC andperiaqueductal gray (C) in the spinomesencephalic tract.

BC=brachium conjunctivum, IC=inferior colliculus, ML=medial lemniscus, NC= centralnucleus of the thalamus, PT=pyramidal tract, PAG=periaqueductal gray, SC= superiorcolliculus, TG= tegmental gray in the brainstem reticular formation, VPL=ventroposetrolateral nucleus of the thalamus.

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The outcome of S activation is increased cardiorespiratory function, constrictionof all or selected vascular beds and mobilization and increased utilization of metabolicfuels. While definitive identification of circuits selectively responsible for these effects isnot complete, a limitied number of forebrain and brain stem areas have been implicated

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in the integration of autonomic sensory input and direct facilitation of S outflow.They are (Figure 19), insular cerebral cortex, paraventricular hypothalamic nucleus(PVN), A5

Figure 19. Brain controls of S outflow

The excitatory brain areas with connections to preganglionic cells in the IML area of thespinal cord are insular cerebral cortex, paraventricular nucleus of the hypothalamus(PVN, plane A), the noradrenergic cell groups in the pons (A5, plane B) and medulla(A1, plane C), and RVLM and caudal raphe nuclei in the medulla (plane C)..

IML=intermediolateral column of the spinal gray matter, PVN=paraventricularhypothalamic nucleus, raphe obscurus and pallidus =caudal raphe nuclei, RVLM=rostral ventrolateral medulla.

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noradrenergic cell group and reticular formation in the pons, andin the medulla, noradrenergic A1 cell group,caudal raphe nuclei (obscurus and pallidus)and reticular rostral ventrolateral medullary nucleus (RVLM). The insular cerebral cortexis involved in emotions of startle, fear and rage that influence cardiorespiratory functionbecause of the connections with the hypothalamic and brainstem sympathoexcitatorycircuit (Cechetto & Saper, 1990). The PVN is thought to be the key coordinator of theentire autonomic outflow (Brown & Fisher, 198 , Luiten et al., 1987, Strack et al. 1989)and through its chemically-coded neurons to play a key role in the regulation of bodyfluids and energy and immune responses (see later). Another hypothalamic area, thedorsomedial nucleus (DMN) has been implicated in patterning of respiratory andlocomotor rhythm during exercise (Eldridge 1985, Marshall & Timms, 1980). Thecatecholamine A1 and A5 cell groups provide noradrenergic input, and A5noradrenergic cells may control regional redistribution of blood from the viscera tothemuscle (Stanek et al, 1984) that occurs during exercise. The caudal raphe nucleiprovide serotonergic activating influence to S outflow. Raphe nuclei also contain TRHand substance-P releasing neurons (Guyenet 1990).

A characteristic of these S centers is that they are tonically active, and the RVLMneurons in the medullary reticular formation that include NE fibers also impose arhythmic discharge pattern to cardiac and respiratory neurons. The RVLM neurons arealso responsible for the vasoconstrictor tone (Gebber 1990, Guyenet 1990, Loewy,1990). The are caudal to the Botzinger complex that initiates and times respiratorymovements (Richter & Spyer, 1990), and this provides a neural basis for the respiratorycontrol over cardiovascular function. The brain areas that generate a S response areintegrative centers that receive both S and PS input, project to both S and PSpreganglionic neurons, and have complex reciprocal connections.

The paraventricular hypothalamic nucleus (PVN) deserves special notice because of itscentral role in coordination of S responses, regulation of energy and fluid balance, andactivation of immune response. The PVN has three functionally differentiated parts thatcan have discrete actions or act together. The lateral part of PVN (and the supraopticnucleus, SO) are magnocellular (Figure 20), and their large cells synthetize hormonesAVP or ADH and oxytocin (OXY), transport them in axons along with neurophysins Iand II that are byproducts of prohormone processing, through the hypothalamo-hypophyseal stalk, and store them in posterior pituitary (Harris & Loewy, 1990). TheAVP and OXY are released into capillaries of the inferior hypophyseal artery and reachsystemic circulation through efferent veins. The magnocellular SO and PVN neuronsdischarge in a characteristic bursting pattern, and their coordinated discharge isfacilitated by cell coupling through tight junctions . The two AVP secreting nuclei receiveprojections from brain areas involved in body fluid regulation and from autonomiccenters that regulate cardiovascular function. Two of the eight circumventricular organs(CVOs) and MPON are structures involved in regulation of body fluids that have neuralconnections with PVN. The CVOs are brain areas without the blood-brain barrier with

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receptors that allow them to monitor chemical changes in systemic circulationand, in

Figure 20. Role of PVN in antidiuresis and cardiovascular control.

The lateral, magnocellular part of the PVN along with the SO nucleusparticipates in release of AVP (and OXY). Sensory information from angiotensin IIreceptors in SFO, from osmoreceptors and sodium receptors in SFO and OVLT andfrom atrial receptors and arterial baroreceptors reaches the PVN and leads to release ofAVP and antidiuretic action on the kidney. At higher stimulus intensities, greateramounts of AVP are released to also influences the cadiovascular system byenhancing baroreflex, increasing neurotransmission in S ganglia, and by causing

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peripheral vasoconstriction. The circumventricular organs (ME, OVLT, PB,PP, OVLT, SCO, and SFO) are shown in the upper left .

AVP= arginine vasopressin, ME=median eminence, OC=optic chiasm, OVLT=organum vasculosum of lamina terminalis, P=pineal gland, PP=posterior pituitary gland,PVN=paraventricular hypothalamic nucleus, SCO= subcommissural organ,SO=supraoptic hypothalamic nucleus.

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some of them, in cerebrovascular space. Among the CVOs, AP is involved in the controlof both food and fluid homeostasis and receives input from carotid baroreceptors,vagus, and dorsomedial and PVN hypothalamic nuclei.

It sends projections to the commissural NTS and PB nucleus (Johnson & Loewy,1990). The OVLT acts as central osmoreceptor and sodium receptor, and SFO hasreceptors for angiotensin II as well as osmoreceptors and sodium receptors. Thecardiovascular involvement of the magnocellular PVN includes a tonic inhibition by atrialreceptors and the baroreceptors, input from A1 noradrenergic cells secreting NE andNPY, C1 adrenergic cells acting on alpha1 receptors, and pontine and tegmentalprojections (Harris & Loewy, 1990).

The AVP is secreted in response to hypovolemia signalled by atrial receptors, tofall in blood pressure detected by arterial baroreceptors, and to increased osmolaritydetected by osmoreceptors. The AVP has two effects, an antidiuretic effect on the V2receptors on distal convoluted tubules in the kidney (hence the term ADH), and athigher concentrations associated with massive fluid losses, a vasoconstrictor action.The vasoconstrictor effect is the outcome of threefold AVP action, on the brain(probably on the CVO AP) where it potentiates baroreflexes (Cowley et al., 1984), onthe sympathetic ganglia where it enhances neurotransmission (Peters & Kreulen, 1985),and on the on V1 receptors on smooth muscle of blood vessels where it causescontraction (Altura & Altura, 1984).

The AVP can also be released in response to activation of pain receptors (groupIII, myelinated and IV, unmyelinated) in muscles and their arteries, or by injection ofbradykinin (Yamashita et al, 1984). This is the probable mechanism of reflex AVPrelease during intense isometric exercise . Reduction in muscle blood flow raisesmetabolite concentration and triggers a reflex increase blood pressure (metaboreflex)through muscle arteriole vasoconstriction caused by both by increased S discharge(Rowell & O'Leary, 1990) and increased AVP release.

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Figure 21. Role of PVN in CRF release and in S elicitation of E secretion.

The medial parvocellular part of the PVN (horizontal hatching) secretes CRF intohypophyseal portal vessels in the external layer of the ME. CRF stimulates release ofACTH from the anterior pituitary, and the ACTH, in turn, stimulates cortisol secretionfrom the adrenal cortex. The dorsal and ventral portions of the PVN (vertical hatching)are involved in activation of S outflow and adrenomedullary E secretion. Cortisol alsostimulates biosynthesis of E in the adrenal cortex, and E stimulates ACTH secretionfrom the pituitary.

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The medial PVN contains small cells ("parvocellular") that synthesize CRF andsecrete this hormone into the hypophyseal portal vessels in the external layer of themedian eminence (ME, Figure 21). The CRF stimulates the anterior pituitarycorticotrophs to secrete ACTH from the POMC precursor (Figure 12). The ACTH, inturn, stimulates cortisol secretion from the fascicular zone of the adrenal cortex (Figure6).

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Figure 22. Role of PVN in activation of immune response.

The PVN controls S outflow to lymphoid organs, spleen, thymus, bone marrow andlymph nodes and release of activated immune cells from lymphoid organs. Monocytesand microphages release IL-I which stimulates CRF release from the parvocellularPVN. IL-1 may reach the PVN through circulation, by paracrine action from monocytesthat migrate out of blood vessels into brain tissue, or from neural hypothalamic circuitsthat use IL-1 as a neurotransmitter. Besides its action on CRF neurons, IL-1 maydirectly stimulate ACTH production from pituitary corticotrophs. The cortisol that isreleased as a result of ACTH stimulation of adrenal cortex, inhibits IL-1 productionprobably through negative feedback at the PVN.

ACTH=adrenocorticotropic hormone, CRF=corticotropin releasing factor, IL-1=interleukin-1.

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The parvocellular part of PVN is sensitive to corticosteroid feedback,and almost all of PVN stimulatory actions on food intake and ingestion of carbohydratesto NE stimulation of alpha2 receptors and to NPY administration (Tempel & Leibowitz,1993) require glucocorticoid presence and feedback. Although the remaining dorsal andventral portions of the PVN are involved in the activation of sympathetic outflow andadrenomedullary E secretion, their elicitation of E release (Figure 22) also depends onpresence and action of CRF (Fisher et al. 1982). In effect, PVN appears to be one of thefew brain centers that regulates the entire S outflow (Strack et al, 1989). In addition tothe facilitatory role of CRF in S outflow from the PVN, cortisol also stimulatesbiosynthesis of E in the adrenal medulla and E stimulates ACTH secretion from thepituitary thus illustrating multiple reciprocal interactions between PVN endocrine andautonomic actions.

The parvocellular PVN also plays two key roles in the control of immuneresponses (Figure 22). As the center controlling the S outflow, PVN is involved in thestimulation of lymphoid organs, spleen, thymus, bone marrow and lymph nodes whichreceive direct S innervation (Friedman & Irwin, 1997). An important outcome of suchstimulation (Hori et al., 1995) during stress and exercise (Mackinnon 1992) is release ofactivated immune cells from lymphoid organs. The interleukin-1, a chemical mesengerreleased from activated macrophages and monocytes, triggers CRF release fromparvocellular PVN (Berkenbosch et al. 1987). The IL-1 may reach PVN throughcirculation, by paracrine action from monocytes and microphages that migrate out ofblood vessels into brain tissue, or from neural hypothalamic circuits that use IL-1 as aneurotransmitter. Thus in stress, the SNS activates the immune response, and theimmune-system chemical messengers stimulate in turn the pituitary stress response.Besides its action on CRF neurons, the IL-1 may directly stimulate ACTH productionfrom pituitary corticotrophs (Ruzicka & Akil, 1995). The cortisol that results from theACTH stimulation of adrenal cortex, inhibits IL-1 production probably through a negativefeedback at the PVN (Uehara et al. 1989).

The cell bodies of S preganglionic neurons are located in the intermediolateralcolumn (IML) of the spinal gray matter (Figure 17). Although there are about 25 pairs ofsegmental paravertebral ganglia extending from the cranial through the sacral end ofthe spinal cord, the preganglionic S nerves leave the spinal cord only through the 12thoracic and the first two lumbar segments and thus form the thoracico-lumbar S outflow(Figure 23). From the IML column, their myelinated axons leave the spinal cord in whitecommunicating rami to synapse on S ganglia. Some preganglionic fibers terminate onneurons in S trunk ganglia. The neurons destined to sweat glands, blood vessels andpiloerector muscles of the skin, leave paravertebral ganglia through the graycommunicating rami and travel in segmental somatic nerves (Figure 17).

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Figure 23. General plan of autonomic ganglia and nerves.

The superior cervical, middle cervical, stellate and about 22 pairs of segmental gangliaform the paired paravertebral S trunks adjacent to the spinal cord. The celiac, superiormesenteric, and inferior mesenteric ganglia are called prevertebral S ganglia (or solarplexus), and they lie some distance from the spinal cord at branching points of theceliac, superior mesenteric and inferior mesenteric arteries from the aorta.Preganglionic S outflow is through the thoracic and the first two lumbar segments.These neurons either form a synapse in the paravertebral ganglia or pass through theseganglia in greater thoracic (gtsn), lesser thoracic (letsn), lowest thoracic (ltsn), andlumbar splanchnic nerves (lsn) to form synapses in prevertebral S ganglia.Postganglionic S fibers then make contact with smooth muscles and glands throughoutthe body. The PS nerves leave the spinal cord in four cranial nerves, oculomotor (III),facial (VII), glossopharyngeal (IX) and vagus (X), and in pelvic splanchnic nerves arisingin sacral spinal cord . The postganglionic PS neurons in the first three cranial nerves

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innervate head and neck glands and smooth muscles, pelvic splanchnic nervesinnervate genital organs and glands and the hind gut, and the vagus nerve all othervisceral organs throughout the body. The geniculate, petrosal and nodose gangliacontain afferent cell bodies of facial, glossopharyngeal and vagus afferent fibers,respectively.

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The first three pairs of paravertebral ganglia, the superior cervical, the middlecervical and the stellate, are located in the neck, from where the postganglionic fibersfrom the first one innervate the eye, the glands and the smooth muscles of the head.When the SNS is activated during exercise or in stress, dilator muscles to the pupilcontract causing pupilary dilatation (Loewy, 1990a). The fibers from the other twoganglia, along with the postganglionic neurons from the first five thoracic ganglia,project to the heart, lungs, bronchi and trachea as the thoracic S cardiac nerves (Figure23).

Some preganglionic S neurons do not form synapses in the paravertebral gangliabut instead travel (Figure 17) in splanchnic S nerves to prevertebral ganglia. Theneurons from fifth through twelfth thoracic segments travel in the greater, lesser andlowest thoracic splanchnic nerves to synapse with postganglionic neurons in the celiacganglion and in the adrenal medulla (Figure 23). Their postganglionic neurons thenreach the foregut and its associated organs and the kidney. The preganglionic neuronsfrom the third and fourth lumbar segments of the spinal cord travel in lumbar splanchnicnerves to the superior and inferior mesenteric ganglia. Their postganglionic neuronsinnervate, respectively, the mid-gut, and the hind-gut and the pelvic organs.

The parasympathetic division of the ANS.

The PS afferents principally convey sensory information from the viscera, thetongue, and the smooth muscle and participate in reflexes controlling lung inflation,heart rate, blood pressure, plasma volume, digestion, and energy regulation. Most ofthis sensory information does not reach cerebral cortex and is not consciouslyperceived. An exception is taste information that is consciously perceived andassociated with affective states, and the role glucose and sodium receptors play inspecific cravings, respectievly for sweet or salty substances in situations of energydeficit and sodium deficiency. The PS afferent fibers are about four times morenumerous than the efferent fibers in the PS nerves (Prechtl & Powley, 1990). The cellbodies of PS afferent neurons are in the ganglia of cranial nerves (for instance,geniculate ganglion of the VII nerve, petrosal ganglion of the IX nerve, and nodoseganglion of the vagus nerve) and in the sacral dorsal root ganglia. The receptorsinnervated by PS afferent fibers include mechanoreceptors, chemoreceptors, specialion (sodium) receptors and hormone receptors.

Four sets of mechanoreceptors monitor blood pressure in peripheral circulation

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(Spyer, 1990). The high-pressure arterial baroreceptors in the carotid sinuses andthe aortic arch, and the renal baroreceptors in the juxtaglomerular apparatus (JGA)sense changes in systemic blood pressure. The low-pressure atrial receptors at theconfluence of great veins with the atria monitor changes in plasma volume and venousreturn to the heart. The stretch receptors in the lungs and the airways react to alveolarstretching. The arterial baroreceptors relay blood pressure information to the centralnervous system (CNS) through the sinus nerve, a branch of glossopharyngeal nerve,and the other mechanoreceptors through the vagus nerve. Different receptors projectboth to discrete regions of the NTS and to a common integrative area (commissuralNTS).

The osmoreceptors, sodium receptors and angiotensin II and atrial natriureticfactor (ANF) receptors for hormones involved in body fluid homeostasis are located inCVOs (Johnson & Loewy,1990). The chemoreceptors monitoring changes in arterialpCO2 and pO2 are located in the carotid body, aortic sinus and the ventral surface ofmedulla oblongata. Additional chemoreceptors are located in the muscles where theymonitor changes in the metabolic state (Kniffki et al. 1981) and promotecardiorespiratory responses to exercise (Kaufman et al 1983).

Chemo- and mechanoreceptors that monitor stimuli associated with ingestionand digestion of nutrients include stretch receptors in the stomach, chemoreceptors inliver, stomach, duodenum, and brain that detect changes in concentration andavailability of nutrients and hormones, and taste receptors. As all but taste are locatedwithin the gastrointestinal tract and associated organs or the brain areas receiving theirafferents, they will be discussed in the section on the ENS.

The taste receptors are chemoreceptors located on the tongue, epiglottis andsoft palate (Figure 24). Taste receptors in the fungiform papillae on the anterior twothirds of the tongue relay sensory information in the chorda tympani nerve, a branch ofthe facial nerve. Taste information from the circumvallate and foliate papillae at the backof the tongue travels in lingual, a branch of the IX th nerve . Additional taste afferentsfrom the epiglottis and soft palate travel, respectively in the vagus and a branch of thefacial nerve. The taste afferents project to the most rostral part of the NTS, from wheresome projections go to the motor nuclei of cranial nerves that control chewing andswallowing, and the others ascend to PB nucleus (pontine taste area), hypothalamus(LH and PVN), limbic forebrain (CNA, BNST, and substantia innominata,SI), and tastearea of the insular cortex (Loewy, 1990).

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Figure 24. Taste afferents and their CNS projections

Taste receptors in the anterior tywo thirds of the tongue, the posterior part of the tongueand the epiglottis and soft palate send afferent fibers, respectively, in branches of VIIth,IXth , and Xth nerves to the rostral NTS. From there taste information ascends to thepontine taste area (BC), hypothalamic nuclei controlling energy balance (LH and PVN),limbic forebrain (CNA, BNST, and SI) and cortical taste area (insular cortex). AC=anterior commissure, BC=brachium conjunctivum, BNST= bed nucleus of the striaterminalis, CNA= central nucleus of the amygdala, CT= chorda tympani, branch of VIInerve, DVN=dorsal vagal nucleus, GG=geniculate ganglion, GP=greater petrosal nerve,branch of VII nerve, LH= lateral hypothalamus, NA= nucleus accumbens, NG=nodoseganglion, NTS= nucleus of the solitary tract, PG=petrosal ganglion, PVN=

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paraventricular nucleus of the hypothalamus, SI= substantia innominata.

Figure 25. Projections of the afferent PS neurons

The PS chemoreceptor and mechanoreceptor afferents project to discrete areas ofthe NTS as well as to a common integrative commissural area of this nucleus. Theascending connections of the NTS are with nuclei in medullary reticular formation(raphe, RVLM, and VMM nuclei); pons (BC, A5); mesencephalic central gray (see

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Figure 19 C); hypothalamus (PVN, DM, and LH); limbic forebrain (CNA andBNST); and insular and prefrontal cerebral cortex. The PS preganglionic neurons inthe DVN and NA receive projections from the cerebral cortex, hypothalamus, midbraincentral gray, pontine nuclei and medullary reticular formation. AP= area postrema,APR=anterior periventricular region, BNST=bed nucleus of stria terminalis, CNA=centralnucleus of amygdala, DM=dorsomedial hypothalamic nucleus, DVN=dorsal vagalnucleus, IML=intermediolateral cell column, LC= locus coeruleus, LH=lateralhypothalamic area, MCG=mesencephalic central gray, MPON=medial preoptic nucleus,NA=nucleus accumbens, NTS=nucleus of the solitary tract, PB=parabrachial nucleus,PVN=paraventricular hypothalamic nucleus, RVLM=rostral ventrolateral medulla,VMM=ventromedial medulla. Planes represent, respectively, A= forebrain septum, B=hypothalamus (diencephalon), C=pons, D=rostral medulla, E=caudal medulla,F=thoracic spinal cord.

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The mechano- and chemoreceptors involved in the regulation ofcardiorespiratory function, the gastrointestinal receptors, receptors in CVOs associatedwith fluid regulation, and taste receptors, all have projections to the NTS and itsimmediate vicinity. From the NTS, ascending nerve fibers make connections with thepontine and forebrain areas (Figure 25.) The cardiorespiratory afferents terminate inadjacent parts of the NTS as well as in a common commissural part of this nucleus.Afferents from the gastrointestinal organs converge in the same area. The areapostrema (AP), one of the CVO that receives information from the hormone, sodium,osmo- and glucoreceptors in plasma and in cerebrospinal fluid, relays this information,as does the commissural NTS to the ascending central autonomic network (Loewy,1990). The main parts of the integrative central autonomic network are, rostralventrolateral (RVLM) nucleus in the medullary reticular formation; lateral parabrachialnucleus (PB) and noradrenergic A5 cell group in the pons; mesencephalic central gray(see Figure 18 C); paraventricular (PVN), dorsomedial (DM) nuclei and lateral area (LH)of the hypothalamus; central nucleus of the amygdala (CNA) and bed nucleus of striaterminalis (BNST) in the limbic forebrain; and prefrontal cerebral cortex.

The PVN, LH, ventromedial hypothalamic nucleus (VMH), CNA and BNST areconsidered to be part of a central integrative autonomic circuit. The CNA connects withthe medial prefrontal cortex that was shown to inhibit cardiorespiratory function(Cechetto & Saper, 1990). The descending projections from the central integrativeautonomic circuit include mesencephalic central gray matter, locus coeruleus (LC), PB,NTS, dorsal vagal nucleus (DVN), nucleus ambiguus (NA), and IML (Luiten et al, 1985).The preganglionic cells of the efferent vagus nerve to the gastrointestinal organs andmuscles of the upper alimentary canal and trachea are in DVN, while vagal cellssupplying the heart and the respiratory muscles originate in the NA (Figure 25).

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The enteric nervous system (ENS) and gastrointestinal hormones.

The ENS is a diffuse network of sensory, internuncial, and motor nerve cells thatthat are located in several layers within the walls of the gut and associated holloworgans (Furness & Costa,1980). Although the heart and blood vessels are excludedfrom this definition, they also have neural plexuses with features similar to the ENS. Thegastrointestinal hormones (Desbuquois, 1990) and their receptors represent the secondchemical messenger system in the GI organs that parallels and communicates withanother similar system in the brain (Pearse, 1969).

Figure 26. Enteric autonomic nerve plexuses

Enteric plexuses in the intestinal wall, moving from the mucosal to the serosal end arethe periglandular, the submucous or Meissner's, the circular intramuscular, themyenteric or Auerbach;'s, the longitudinal intramuscular, and the subserous plexuses.

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The gastrointestinal organs are supplied with receptors that monitor mechanicaland chemical changes associated with ingestion and digestion of food. After the initialchemical stimulation of taste receptors, gastric distension is sensed by the stretch

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receptors in the stomach wall ( Berthoud & Powley, 1992), and glucoreceptors(Nagase et al., 1993), amino acid receptors (Niijima & Meguid, 1995), osmoreceptors(Niijima, 1969) and sodium receptors (Contreras & Kosten, 1981) have been describedin the liver (Lautt, 1980). The duodenum also has gluco- and sodium receptors (Walls etal., 1995), and receptors for several hormones appear to be located on the on vagalterminals or cell bodies of vagal efferents, among them cholecystokinin (CCK, Ritter etal., 1989), angiotensin II (Speth et al., 1987 ) , galanin (Calingasan & Ritter, 1992b) andothers.

The enteric plexuses in the intestinal wall, moving from the mucosal to theserosal end are the periglandular, the submucous or Meissner's, the circularintramuscular, the myenteric or Auerbach;'s, the longitudinal intramuscular, and thesubserous plexuses (Figure 26). In the heart, there are cardiac and coronary plexuses.The intrinsic neurons in the autonomic plexuses use several peptidergic messengers(Pearse 1969, Costa et al. 1986). Most common in the submucous and myentericplexuses are neurons using VIP and enkephalin as messengers, and CCK is the leastcommon. Other neuropeptides in the ENS are somatostatin or somatotropin-release-inhibiting factor (SRIF), dynorphin, NPY, substance-P and serotonin, and frequentlymore than one peptide is colocalized in the same neuron. There is differential chemicalcoding of neurons located in different GI plexuses (Costa et al. 1986).

As is the case with other targets of ANS, ENS receives dual afferent and efferentinnervation from SNS and PNS. The S afferents and efferents reach the GI organsthrough several sympathetic splanchnic nerves (Figure 23). The NE fibers inhibit GImotility and ganglia embedded in the plexuses and increase contraction of sphincters.The SNS fibers colocalizing with NPY vasoconstrict splanchnic circulation, and thefibers containing NE and somatostatin inhibit GI secretion (Costa et al. 1986). The PSafferents and efferents innervate the foregut and midgut through the vagus, and thehindgut and reproductive organs through the pelvic splanchnic nerves. The PS gangliaand postganglionic cells are embedded within the ENT plexuses (Willems et al. 1985).The cholinergic fibers stimulate myenteric (Holst et al. 1997) and submucous ganglia(Berthoud et al., 1991), gastric motility, and GI secretory activity.

The mucosa of the stomach and intestine contains endocrine cells that produce anumber of different hormones (Desbuquois, 1990). Serotonin and somatostatin-secreting cells are found throughout the entire extent of GI tract. The cells producingsecretin, cholecystokinin (CCK), gastrin colocalized with CCK, beta-endorphin,neurotensin, and gastric inhibitory peptide (GIP) are mostly found in duodenum andjejunum, and glucagon-secreting cells are more prevalent in jejunum, ileum, and colon.Most of the GI cells producing hormones communicate by endocrine route, and secretinwas the very first hormone discovered by Bayliss and Starling in 1902. Some GIhormones are distributed by endocrine as well as paracrine route (SRIF), and a few ofthem are also released into the GI lumen (gastrin, SRIF, secretin).

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The function of GI hormones is to control digestion of food and GIgrowth. The digestion is achieved through the control of gut motility, splanchniccirculation, modulation of the pH of the chyme (mixture of food and gastric secretions),and secretion of enzymes and hormones. The hormones that increase GI motility aremotilin, SP, CCK, and enkephalins, while secretin, glucagon, VIP, GIP, NPY, andneurotensin inhibit it. Almost all of the GI hormones stimulate GI blood flow, particularlySP and neurotensin, except NPY which is a potent vasoconstrictor.

Figure 27. GI endocrine reflexes in control of digestion

Serial elicitation of GI hormone release by the passage of food through the GI tract.Food elicits gastrin release, and fat and protein the release of CCK. Both hormonesstimulate gastric motility and CCK causes contraction of gall bladder and release of bileacids necessary for the emulsification of fats. Gastrin action is to release hydrochloricacid as the preliminary step in digestion of proteins. The acidity of chyme is the stimulusfor secretin release from duodenum, and its action is to trigger secretion of bicarbonateand digestive enzymes from the pancreas. Many GI hormones facilitate the release ofinsulin with the exception of SRIF which inhibits it. The GI hormones released early inthe digestive process stimulate release of other GI hormones. Those released late inthe digestive process inhibit the secretion of GI hormones.

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Food digestion is facilitated by a series of GI endocrine reflexes (Figure 27). The

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ingested food constitutents are the principal stimulus for the release ofgastrin, CCK, motilin, GIP, SRIF, and neurotensin, and in the case of CCK, fats andamino acids. These hormones are released serially according to their regionaldistribution throughout the GI tract. The initial release of gastrin results in secretion ofhydrochloric acid which lowers the pH of the chyme to 2 and aids in the initial digestionof proteins. Increased acidity of chyme is the stimulus for the subsequent release ofsecretin, the effect of which is secretion of bicarbonate (and of digestive enzymes) fromthe pancreas and the restoration of neutral pH of the chyme. The dietary fats trigger therelease of CCK, and the main CCK action is to release bile acids from the gall bladderand assist in emulsification and digestion of fats. The food also triggers secretion ofSRIF throughout the GI tract and of enteroglucagon from the colon. These twohormones as well as serotonin, inhibit secretion of gastrin and of gastric acid secretion.SRIF also inhibits secretion of all other GI and pancreatic hormones. The presence ofSRIF is necessary for the GIF, VIP, and GIP to inhibit gastrin release. All GI hormonesstimulate secretion of pancreatic insulin, pancreatic polypeptide (PPP), glucagon, andSRI, known also as the incretin effect. Thus GI hormones that are released early in thedigestive process facilitate the release of GI and pancreatic hormones releasedsubsequently, and the action of hormones released later in digestive process is toterminate the early steps of this endocrine cascade (Figure 27).

Autonomic reflexes.

The simplest form of autonomic action is a reflex. A number of reflexes controlledby the ANS operate autonomously or as part of complex neuroendocrine and behavioralresponses to disturbance in the internal environment. Some of the more commoncardiorespiratory and endocrine reflexes are listed below .

Atrial mechanoreceptor reflex is a response to change in plasma volumedetected by the low-pressure baroreceptors at the junction of venae cavae with theatria. The Increases in venous return produce bradycardia and reduced vasomotor tone,particularly to the kidney, and diuresis. The latter is in part a result of increasedglomerular filtration rate and in part a response to the reflex release of atrial natriureticpeptide (ANP).

Baroreflex normalizes systemic blood pressure when it has deviated outside thenormal range (Spyer, 1990). The discharge rate of the carotid and sinus nerve afferentfibers innervating arterial high-pressure baroreceptors is directly proportional to arterialblood pressure and triggers reflex reduction in peripheral vasoconstriction, particularly inthe muscle and less so in the skin, and in heart rate (bradycardia) and heart contractility(Figure 28). The reflex arc entails a baroreceptor afferent projection to NTS and anefferent vagal output from NA. At the same time baroreceptors exert an inhibitoryinfluence over the S cardioaccelerator nerves by way of internuncial neurons in themedial prefrontal cortex and CNA that suppress the rhythmic cardiac and vasomotordrive from the medullary reticular formation (RVLM and raphe nuclei).

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Figure 28. The baroreflex

The discharge rate of carotid sinus and aortic arch baroreceptors is proportional toarterial blood pressure, while in the S cardiac nerves it is inversely proportional. The cellbodies of the afferent neurons innervating the two baroreceptors are, respectively, inpetrosal and nodose ganglia and their dendrites project to NTS in sinus and aorticnerves. The inhibition of the heart rate and contractility, and reduction invasoconstriction of blood vessels, is carried out by vagus with preganglionic neurons inNA. Baroreceptors also activate internuncial neurons that inhibit the RVLM nucleus, theorigin of cardiovascular S drive.

NA= nucleus accumbens , NG=nodose ganglion of the X nerve , NTS=nucleus of thetractus solitarius, PG=petrosal ganglion of the IX nerve, RVLM=rostral ventrolateral

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medulla, S=sympathetic

Chemoreceptor reflex is a response to reduced arterial oxygen partial pressure(pO2) detected by aortic sinus and carotid body chemoreceptors and to increasedcarbon dioxide partial pressure (pCO2 ) monitored by cells on the ventral surface of themedulla. It corrects these deviations through increases in minute ventilation (VE) andcardiac output (Q), and to a lesser extent through changes in vasoconstriction. Theinternuncial integrative circuits involve (Richter & Spyer, 1990) cardiovascular andrespiratory nuclei in the medulla (Figure 25, planes D and E) that act in coordinated andcooperative fashion, and the inhibitory vagal influence from the NA . Neurons inBotzinger complex that are responsible for initiation and timing of respiratory rhythmsareadjacent and rostral to the RVLM nucleus that initiates and times cardiovascularfunction so that functional interactions, and subordination of cardiovascular function torespiratory control, as is the case in diving reflex, has an anatomical basis. Thepatterning of cardiovascular and respiratory responses during exercise is also linkedand apparently controlled by posterior hypothalamus or dorsomedial hypothalamus(Eldridge et al., 1985, Saper et al., 1976, Wardrop et al., 1988).

Diving reflex entails vagal suppression of the Q and of respiratory drive andbronchoconstriction, mediated by the vagus nerve (Kawakami et al. 1967, Kobayashi &Ogawa, 1973). The PS afferent discharge in the facial (VII) nerve to cooling of the faceinitates the reflex that subordinates the chemoreceptor signals of reduced pO2 andincreased pCO2 to respiratory breath-holding. Reflex is well expressed in divingmammals and less so in humans.

Metaboreflex entails vasoconstriction in response to build-up of metabolicproducts in the muscle during ischemia that is associated with isometric musclecontractions. It was described in the preceeding section.

Orthostatic or postural reflex entails redistribution of blood to the head and upperregions of the body after a change in body position from recumbent to upright. It utilizesafferent input from baro- atrial mechano- and chemoreceptors. Postural hypotension isthe condition where the orthostatic reflex operates sluggishly causing transient cerebralischemia and dizziness.

Sudomotor reflex also is a component of thermoregulatory response. It involvesreflex activation of eccrine sweat glands by the cholinergic sympathetic neurons.Temperature change is detected by somatic temperature-sensitive neurons in the skinor in the central nervous system. A greater change in internal or external temperature isrequired to elicit this reflex than the vasomotor reflex (Stolwijk & Hardy, 1977).

Vasomotor reflex is a component of thermoregulatory response. It involves reflexchanges in the degree of vascular constriction in response to changes in blood orambient temperature and in selective constriction of peripheral or deep limb veins inresponse to cold or hot stimulus, respectively. Changes in vascular tone are achieved

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through variation in the degree of vasoconstrictive S action. Temperaturechange is detected by somatic temperature-sensitive neurons in the skin or in thecentral nervous system. Selective activation of S motoneurons to skin blood vesselsand not to muscle vascular beds is controlled by the A5 noradrenergic cell group(Stanek et al., 1984, Figure 25, plane C) and by the RVLM nucleus (Dampney &McAllen, 1988, Figure 25, plane D) in response to thermoregulatory challenge.

The central control of thermoregulatory reflexes involves integration of afferentinput from central and peripheral thermoreceptors. Hypothalamic nuclei that also controlbody fluid balance and hypothalamic areas responsible for S activation and heatproduction are involved in the interaction, but the anatomical and functional details arepoorly understood (Strand et al 1986).

Autonomic control of endocrine reflexes.

There are numerous and complex reciprocal interactions between the ANS andthe endocrine systems. Only a few of these interactions will be mentioned here to showtheir relationship to the ANS function. Additional details and more extensive discussionof these reflexes can be found in the chapters dealing with receptor mechanisms (3),exercise as an emergency (4), regulation of fuel use during exercise (5), andtemperature and fluid balance during exercise (8).

Adrenomedullary catecholamine release. The adrenomedullary catecholaminerelease is triggered by the action potentials in preganglionic neurons originating in thelast three thoracic and first lumbar spinal segments (Figures 21, 23) that reach theadrenal medulla through the lesser and lowest splanchnic sympathetic nerves. Theycommunicate through transmission of ACH and act on nicotinic receptors. Somepreganglionic neurons form synapses in the celiac ganglion and send postganglionicfibers to blood vessels supplying the adrenal gland. They release NE and act on alphaadrenergic receptors. Adrenal medulla also receives PS innervation through the twoceliac branches of the vagus nerve (Berthoud & Powley, 1993). The central control ofadrenomedullary hormone release (Edwards, 1990) is mediated by hypothalamic (PVN,Figure 19, plane A) and medullary nuclei (caudal raphe, RVLM, VMM, and A5, Figure19, planes B and C). This reflex is elicited by glucoprivation with concurrent supressionof the S activity (Egawa et al. 1989, Ritter et al. 1995) , a response that is mediated bythe PVN (Katafuchi et al. 1988). This reflex is elicited during exercise together withactivation of the SNS (Young & Landsberg, 1983).

The adrenomedullary catecholamines have cardiorespiratory and metabolicactions. Both E and NE can activate either of two principal types of adrenergicreceptors, alpha and beta, but NE has higher affinity for alpha receptors while E hashigher affinity for beta receptors (Parkinson, 1990). Receptor distribution varies bytissue types, which together with differential receptor affinities for the two hormonesallows for diverse biological effects. The two principal receptor types can be subdivided

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into several variants. Table 6 lists the principal adrenergic receptor types, theirbiological effects, and some commonly used receptor agonists and antagonists..

Figure 29. Renin-angiotensin-aldosterone reflex

When blood pressure declines, renal S nerve triggers and potentiates renal release ofrenin to hypovolemic stimulus. Renin converts circulating angiotensinogen intoangiotensin I. The endothelial converting enzyme transforms the angiotensin I intoangiotensin II. The angiotensin helps expand plasma volume through three actions. It

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stimulates release of aldosterone from the adrenal cortex with the consequentincreased renal sodium reabsorbtion. It binds to the SFO, one of the circumventricularorgans and stimulates the magnocellular hypothalamic nuclei (SO,PVN) to releaseADH. Finally it enhances neurotransmission in the S celiac ganglion which causes renalvasoconstriction and reduced glomerular filtration rate.

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The adrenomedullary and adrenocortical hormones have reciprocal interactions.While cortisol permits E synthesis, E stimulates pituitary ACTH release which in turntriggers cortisol release (Figure 21). This positive feed-back loop may operate understressful conditions, including extreme exercise, when actions of both hormones arecomplementary and beneficial.

Antidiuretic endocrine reflex of the posterior pituitarywas described in the context ofmagnocellular PVN functions

Reflex release of plasma renin to hypovolemia. The loss of sodium from theextracellular compartment with the consequent reduction in plasma volume is sensed bythe baroreceptors in the JGA, the specialized contact area between the ascending limbof the kidney tubule (macula densa) and the afferent arteriole to the glomerulus. Therenal S nerve activity triggers renin secretion and potentiates its release to hypovolemicstimuli (Kopp & DiBona, 1993, Saxena et al., 1992). The granular cells of the afferentarteriole secrete renin, the principal action of which is to catalyze conversion of plasmaangiotensinogen into angiotensin I (Figure 29). The converting enzyme in the vascularendothelia converts angiotensin I to the biologically active angiotensin II. Angiotensin IIstimulates secretion of aldosterone from the external glomerular zone of the adrenalcortex and thereby increases reabsorbtion of sodium from tubular lumen into plasma. Italso potentiates the neurotransmission in the celiac ganglion causing renalvasoconstriction and reduced glomerular filtration rate. The angiotensin II binds to theSFO and stimulates PVN and SO nuclei to release ADH. By increasing sodium andwater reabsorbtion and reducing glomerular filtration, this reflex leads to expansion ofplasma volume. Finally, this messenger elicits both thirst and sodium hunger by actingon the CVO angiotensin II receptors.

Autonomic control of pancreatic hormone release. The endocrine pancreas isinnervated by the preganglionic vagal fibers originating in DVN, preganglionic S fibersfrom fifth through ninth thoracic segments and postganglionic S fibers originating in theceliac ganglion. During exercise or other circumstances that elicit increased S outflow,NE from S nerve terminals inhibits insulin secretion by acting on alpha2 receptors onbeta cells of pancreatic islets and stimulates glucagon and SRIF release by acting onalpha1 and beta receptors located on alpha and delta cells, respectively (Edwards,1990). The stimulation of beta adrenergic receptors has a stimulatory effect on insulinrelease. The integrative centers needed for the reflex increases in hepatic

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glycogenolysis and in E and glucagon release during glucoprivation are NTS,lateral PB, LC, AP, PVN, and DVN ( Ritter & Dinh, 1994) with the NTS and AP playingthe more critical role (Calingasan & Ritter, 1992 a). The PVN also is the site of receptorswhere NE, NPY and cortisol increase (Tempel & Leibowitz, 1993), and serotonin(Leibowitz et al. 1993) and CRF decrease carbohydrate intake (Bray 1993) afterglycogen depletion. Reduced oxidative utilization of lipids is monitored by different set ofperipheral receptors, peptide mediators (Akabayashi et al. 1994) and brain nucleigoverning selection of dietary fat (Ritter & Dinh, 1994).

During ingestion of food, cephalic-phase insulin secretion occurs before thearrival of absorbed food into the blood. It is triggered by hepatic and intestinalglucoreceptors and the respective branches of vagus (Berthoud & Powley, 1990). Uponabsorbtion, increased plasma concentrations of nutrients directly stimulate insulin,glucagon, and pancreatic polypeptide secretion and inhibit SRIF release .In addition,intestinal and hepatic glucoreceptors elicit reflex vagal stimulation of insulin andglucagon secretion by acting on cholinergic muscarinic receptors while the activity ofhepatic splanchnic nerve is decreased . Concurrently the hepatic branch of the vagus isalso activated and stimulates glycogen synthesis (Niijima, 1989).

The role of autonomic nervous system in exercise.

From the preceding discussion of the functional properties of the ANS it is nowpossible to highlight its several important roles in exercise. In evaluating the evidencefor the role of ANS in exercise it is useful to be reminded of limitations of differentmethods used to assess ANS activity. Direct measurements of catecholamines incirculation do not identify the relative contributions of the SNS and the adrenal medulla,as the medulla secretes both catecholamines, and at high exercise intensities, NE(Leuenberger et al., 1993) and NPY (Kaijser et al., 1994) spill over from the nerveendings into plasma. Without additional information about NE appearance andclearance rates, circulating concentrations give limited information.

Measurements of arteriovenous NE differences circumvent this limitation. Dailyurinary catecholamine output is another valid way to quantify sympathoadrenal activitybut is of limited use in studies examining S control in exercise. Pharmacologicalblockade and stimulation can yield useful information when direct effects of suchmanipulations on physical performance are assessed and controlled. An indirectmethod of estimating PS and S activity in exercise is spectral analysis of heart ratevariability (Yamamoto & Hughson, 1991). It entails separating total spectral power (Pt)of HR variability into harmonic and nonharmonic components, and harmonic componentinto high (Ph) and low frequencies. (Pl). The ratios of Ph/Pt and Pl/Pt then representrespective measures of PS and S effects on the heart, and by implication on the rest ofthe body. Direct measurements of S nerve activity have also been done on the limbs(Saito, 1995).

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The three most important roles of the ANS in exercise are, itscoordination of several different physiological functions during exercise, its capacity toincrease physiological responses in anticipation of actual needs, and its capacity tomaintain constancy of the internal environment by compensating for the perturbationscaused by exercise. The integrative role of catecholamines is inherent in their ability todirectly affect a number of different processes. The SNS and the adrenal medullaryhormones control the chronotropic (HR) and inotropic (heart contractility) functions ofthe heart, contraction of vascular beds and as a consequence, blood pressure andredistribution of blood from the splanchnic beds to muscle during exercise. The SNSand the adrenal medullary hormones also control mobilization and utilization ofmetabolic fuels, and reflecting the evolutionary function of physical activity in fight orflight situations, controls over defense reactions such as aggregation of platelets (Larsson et al., 1994) that is important in blood clotting, and activation of cells mediatingimmune responses. The ANS contributes also to general arousal, increased pupillarydiameter, piloerection, and release of endogenous opiates that have analgesicfunctions. Finally, the sympathoadrenal system engages other endocrine systems insupport of its cardiorespiratory, circulatory and metabolic functions in exercise, andthese will be explored in greater detail in later chapters.

The anticipatory function of the ANS is seen in increased cardiorespiratoryfunction prior to the onset of physical activity (Mason et al., 1973) and in the dose-dependent release of catecholamines in proportion to the intensity or stressfulness ofexercise. While both the S nerve activity and adrenal catecholamines increase withexercise intensity (Figure 30) , E requires greater stimulus intensities for its release thanis the case for S activation. The PS tone declines at low exercise intensities (Nakamuraet al. 1993) and increases during the recoveryphase when it can lead to post-exercisefall in blood pressure (Halliwill et al.,1996) or increase in anabolic and biosyntheticfunctions. The systematic relationship with exercise intensity is also seen in a number ofhormones that are released during exercise and are influenced by S nerve activity suchas dose-dependent decreases in plasma insulin and increases in secretion of glucagon(Saltin & Gollnick, 1988 ), cortisol , ACTH , aldosterone (Luger et al., 1988 ), AVPamong others.

The third important role of the ANS in exercise is its regulation of the internalenvironment during exercise and recovery from exercise. During exercise, homeostaticcontrol mechanisms often undergo readjustment to meet increased functional demandsof exercise. For instance baroreflex is reset to a higher pressure level to operate atincreased blood pressure ranges encountered during exercise ( Rowell & O'Leary,1990). As exercise creates disturbances in the internal environment, the ANS generatescorrective reflexes or more complex responses. The priorities for maintenance ofdifferent aspects of the internal environment shift during exercise. Increased heatgenerated by muscle activity leads to excessive heat gain which is counteracted byvasomotor and sudomotor reflexes and appropriate thermoregulatory behaviors. As a

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consequence of increased sweating, an imbalance develops in body fluid volume.Conservation of plasma volume through AVP or renin-angiotensin-aldosterone reflexesnow assumes higher priority than the regulation of body temperature.

Figure 30. Time course and dose-dependence of the sympathoadrenal responses toexercise

A conceptual illustration of changes in the relative activities of S and PS nervesand in secretion of adrenomedullary E as a function of intensity or duration of exerciseand during recovery from exercise. At the start of exercise, PS tone declines and istransiently increased during recovery when it participates in restorative biosyntheticactions. At the start of exercise, S tone increases in proportion to intensity orstressfulness of exercise. Higher exercise intensities are required to elicit E secretionwhich also is secreted in dose-dependent fashion. The decay of S nerve activity isfaster than the disappearance of E from circulation.

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The control by the sympathoadrenal system of fuel mobilization and use duringexercise changes as a function of exercise intensity and duration (Young & Landsberg,1983). These changes reflects variable contributions of alpha and beta receptorstimulation as the relative activities of S nerves and adrenal E change under differentconditions of exercise. During the early stage of exercise or at low exercise intensities,increased S nerve activity and NE release from the nerve terminals (Figure 30) results

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in predominant stimulation of alpha adrenergic receptors in the liver and theadipose tissue (Table 6). These conditions facilitate hepatic glucose production via thegluconeogenic Cori cycle, increased muscle glucose uptake and glycolysis and lowlevel of lipid utilization due to inhibitory alpha adrenergic effects on lipolysis and lack oftransport of FFAs from vasoconstricted splanchnic vasculature.

As the intensity or duration of exercise increase (middle part of Figure 30), fuelmetabolism is controlled by both increased S nerve activity and adrenal E secretion.Catecholamines now stimulate glycogenolysis in the liver and in the muscle. In additionto glycolysis, beta receptor activation stimulates carbohydrate oxidation. The alphaadrenergic ation on the Cori gluconeogenic cycle is at its peak, so that this phase ofmetabolism is characterized by carbohydrate dependence. At this stage, increased betaadrenergic stimulation accelerates lipolysis in the adipose tissue and removes theperipheral circulatory restraints over FFA release. This permits greater access ofalbumin-bound FFAs to plasma and exercising muscle.

Table 6

Principal types of adrenergic receptors

ALPHA 1 ALPHA 2 BETA 1 BETA 2

vasoconstriction vasoconstriction ∧ heart rate broncholdilatationvasodilatation

∧ heart contractility ∨ NE release ∧ heartcontactibility

glycogenolysis(L,M)

gluconeogenesis ∨ lipolysis ∧ lipolysis glycolysis

glycogenolysis (L) ∧ plateletaggregation

renin release oxidativemetabolism

∧ nutrient uptake ∨ insulin release ∧ insulin release

glycolysis amylase secretion

sweating

piloerection AGONISTS

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salivation salbutamol

AGONISTS AGONISTS AGONISTS# rimiterol

methoxamine clonidine* prenaterol albuterol

phenylephrine alpha-methyl-NE tolbutamine terbutaline

tramazoline tazolol hexoprenaline

xylazine dobutamine soterenol

zinterol

clenbuterol

ANTAGONISTS ANTAGONISTS ANTAGONISTS salmotamol

prazosin yohimbine ICI 89, 407 procaterol

BE 2254 idazoxan paraoxyprenolol epinephrine

corynanthine rauwolscine betaxolol

phetolamine phentolamine atenolol ANTAGONISTS

practolol ICI 118,551

metoprolol IPS 338

propranolol butoxamine

propranolol

#Beta 3 receptor has high affinity for the lipolytic action of NE (Yamashita et al., 1993)

When exercise intensity is not above the anaerobic threshold, the next stage ofexercise favors oxidative utilization of lipids. The shift from carbohydrate to lipidoxidation in the muscle is facilitated by the glucose-fatty acid cycle (Newsholme, 1977) ,low insulin concentration, and by reduced muscle sensitivity to alpha adrenergicstimulation as a consequence on increased FFA delivery to the muscle (Burns et al.

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1978). The pattern of sympathoadrenal activation favors lipid utilization undertheses conditions of exercise.

During recovery from short-term exercise, there is a rapid rise in plasma insulin(Wahren et al. 1973), probably reflecting a decline in S activity and an increase in PStone. This contributes to the fall in hepatic glucose output and increased glucose uptakeby the muscle. During recovery from long -term exercise that has resulted in glycogendepletion and in a fall in plasma glucose, plasma insulin remains low andadrenomedullary release of E and secretion of glucagon are sustained. Thus the Sadrenomedullary and pancreatic reflexes here compensate for the deficiencies inregulation of plasma glucose and permit a more extended hepatic glucose productionby gluconeogenesis (Bjorkman & Wahren, 1988).

Habitual physical activity produces adaptations in sympathoadrenal function.There is a decrease in plasma NE responses and adrenal E release (Hartley et al. 1972) and increased PS tone (Goldsmith et al., 1993) at equivalent exercise loadssuggesting an active supression of S tone and facilitation of PS tone. The ANS thuscontrols acute functional adjustments to oxygen and energy needs during acuteexercise bouts and participates in physiological adaptations to sustained high levels ofphysical activity.

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